Medicaments containing doxazosin mesylate of crystalline modification D

ABSTRACT

Drugs comprising modification D of doxazosin mesylate are described. They are suitable for treating high blood pressure.

The present invention relates to a drug comprising doxazosin mesylate incrystal modification D.

Doxazosin(=4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1yl-]6,7-dimethoxyquinazoline)is a known substance (Merck Index, 12^(th) edition 1996, No. 3489) whichlowers blood pressure. The substance is mainly used in the form of themonomesylate which, in crystalline form, occurs in severalmodifications. Thus, three crystal modifications which are referred toas modifications A, B and C are described in the Chinese Journal ofMedicinal Chemistry 5(4), 266-270 (1995). Modification A is obtained onrecrystallization of doxazosin mesylate from ethanol. Modifications Band C result on recrystallization of doxazosin mesylate from chloroformand water respectively. Mention may be made of the fact that the ChineseJournal of Medicinal Chemistry in fact speaks simply of doxazosin.However, according to the published data, the material must be doxazosinmesylate. Modification A is also the subject of EP-A 0 849 266, where itis referred to as form III.

Another modification has been described and characterized in EP-A 0 848001, but it was not given a special name. EP-A 0 849 264 describes aform I and EP-A 0 849 265 describes a form II of doxazosin mesylate.

The patent application PCT/EP/98/08360 (filed on Dec. 18, 1998),unpublished at the priority date of the present specification, describesa form D of doxazosin mesylate which occurs as intermediate in thepreparation of form A of doxazosin mesylate.

It has now been found that modification D of doxazosin mesylate can beused particularly satisfactorily as a drug for high blood pressure.

The invention relates to drugs comprising modification D of doxazosinmesylate and the use of modification D of doxazosin mesylate forproducing drugs for high blood pressure.

Modification D of doxazosin mesylate is prepared by dissolving doxazosinwith methanesulfonic acid in methanol, removing any turbidity from theresulting solution, stirring the resulting clear solution until nofurther precipitate is formed, and removing the precipitate and washingit with methanol and drying it.

To react doxazosin with methanesulfonic acid, the two substances areemployed in the molar ratio of about 1:1. It is preferred to use a smallmolar excess of sulfonic acid (up to about 10%).

If the time between the obtaining of a solution by addition ofmethanesulfonic acid to the doxazosin and the appearance of aprecipitate is insufficient for a filtration—for example when thereaction is to be carried out on the industrial scale—the time for thefiltration can be extended by adding an aprotic polar organic solvent tothe methanol used for the reaction.

Examples of aprotic polar organic solvents suitable in this case areN,N-dimethylformamide and, in particular, N-methyl-2-pyrrolidone. Theratio of doxazosin to methanol (weight/volume) or the ratio of doxazosinto methanol to the aprotic polar organic solvent (weight/volume/volume)is about 1: (5 to 15), preferably about 1:(8 to 12) or about 1:(5 to 15)(1.5 to 4), preferably about 1:(8 to 12):(2 to 3).

If in the process the solution obtained after the addition ofmethanesulfonic acid has to be filtered to remove any foreign particlespresent, it is preferred to use the solvent mixture comprising aproticpolar organic solvent and methanol. The reason is that in this case, asalready mentioned, the time between the obtaining of the solution andthe formation of the first crystals is greater than with the use ofmethanol alone as solvent. If filtration of the solution obtained afterthe addition of methanesulfonic acid is desired in the process, aparticularly preferred procedure comprises using the solvent mixture ofaprotic polar organic solvent and, moreover, adding part of the methanolonly after the filtration.

Modification D of doxazosin mesylate is characterized in particular byprincipal lines in the Debye-Scherrer X-ray diffractogram at thefollowing values of 2 theta stated in degrees: 5.72±0.2°; 11.10±0.2°;11.46±0.2°; 14.14±0.2°; 17.01±0.2°; 17.78±0.2°; 18.33±0.2°; 20.73±0.2°;21.70±0.2°; 23.12±0.2°; 24.28±0.2°; 26.58±0.2°.

Modification D of doxazosin mesylate has the advantage that it can beprocessed to tablets more easily. Thus, this modification shows verygood miscibility with other substances and an excellent mixing behavior.The very good flow characteristics of the novel modification furtherfacilitate the production of solid pharmaceutical forms.

EXAMPLES Preparation of Doxazosin Mesylate of Crystal Modification D

Process a

14.1 g of anhydrous methanesulfonic acid were added to a stirred mixtureof 63.2 g of doxazosin, 125 ml of N-methyl-2-pyrrolidone and 500 ml ofmethanol in a 1 1 three-necked round-bottomed flask. During this timethe internal temperature rose to 30° C., and a solution formed. Afterthe addition of the methanesulfonic acid was complete, the reactionmixture was filtered into a second 1 1 three-necked round-bottomedflask. The filter was washed with 85 ml of methanol, and the combinedfiltrates were stirred for 5 h. After completion of the stirring time,the resulting precipitate was filtered off with suction and washed 3×with 25 ml of methanol each time. 125 g of moist doxazosin mesylate(modification D) were obtained. This corresponds to 70.4 g of drysubstance and a yield of 91.8%.

Modification D of doxazosin mesylate was characterized by theDebye-Scherrer X-ray diffractogram, by the differential scanningthermogram and by the IR spectrum (cf. FIGS. 1-3; see above for the2-theta values of the principal lines in the diffractogram). All thedata were obtained for vacuum-dried material.

Process b

6.1 g of anhydrous methanesulfonic acid were added to a stirred mixtureof 27.1 g of doxazosin, 54 ml of N-methyl-2-pyrrolidone and 250 ml ofmethanol in a 500 ml three-necked round-bottomed flask. During this, theinternal temperature rose to 30° C., and a solution formed. After theaddition of the methanesulfonic acid was complete, the reaction mixturewas filtered into a second 500 ml three-necked round-bottomed flask, andthe filtrate was stirred for 5 h. After completion of the stirring time,the resulting precipitate was filtered off with suction and washed 2×with 50 ml of methanol each time. 45 g of moist doxazosin mesylate(modification D) were obtained. This corresponds to 28.5 g of drysubstance and a yield of 86.7%.

Process c

17.7 g of anhydrous methanesulfonic acid were added to a stirred mixtureof 79.0 g of doxazosin and 800 ml of methanol in a 2 1 three-neckedround-bottomed flask. During this, the internal temperature rose to 30°C., and a solution formed. After the addition of the methanesulfonicacid was complete, the mixture was stirred for a further 5 h. Theresulting precipitate was then filtered off with suction and washed 3×with 50 ml of methanol each time. 141.8 g of moist doxazosin mesylate(modification D) were obtained. This corresponds to 89.2 g of drysubstance and a yield of 93.1%.

Examples of Pharmaceutical Forms

121 g of doxazosin mesylate (form D), 5 g of Aerosil® (highly dispersedsilica) and 874 g of spray-dried lactose were mixed together, and theresulting mixture was ground and triturated in a laboratory pinned diskmill. It was important to produce a trituration so that the tabletsmaintain good content uniformity. The trituration obtained in this waywas used as base mix for the following formulations:

A. Tablets Containing 1 mg of Doxazosin Mesylate (Modification D)

10 g of the base mix were mixed with 89 g of Ludipress® (excipientpreparation from BASF Aktiengesellschaft) and 1 g of magnesium stearateand compressed in an eccentric press with a tablet punch diameter of 7mm under a force of 8 kN to tablets weighing 100 mg and having ahardness of 80 N. The active ingredient content per tablet was 1.21 mgof doxazosin mesylate, equivalent to 1 mg of doxazosin base. Theresulting tablets disintegrated within 2 min in water at 20° C. Theactive ingredient release after 20 min was 85%.

B. Tablets Containing 2 mg of Doxazosin Mesylate (Modification D)

Tablets weighing 200 mg were produced as in A. They were compressedusing a punch with a diameter of 9 mm under a force of 9 kN and had ahardness of 60 N. The doxazosin mesylate content of the tablet was 2.42mg, equivalent to 2 mg of doxazosin base. The tablets obtained in thisway disintegrated within 3 min in water at 20° C. The active ingredientrelease after 20 min was 81%.

C. Tablets Containing 4 mg of Doxazosin Mesylate (Modification D)

20 g of the base mix were mixed with 79 g of Ludipress® (excipientpreparation from BASF Aktiengesellschaft) and 1 g of magnesium stearateand compressed in an eccentric press with a tablet punch diameter of 9mm under a force of 8 kN to tablets weighing 200 mg and having ahardness of 50 N. The active ingredient per tablet was 4.84 mg ofdoxazosin mesylate, equivalent to 4 mg of doxazosin base. The resultingtablets disintegrated within 4 min in water at 20° C. The activeingredient release after 20 min was 80%.

The release in vitro was determined by the following method:

The tablets were tested for their active ingredient release in a paddleapparatus complying with USP XXIII with 6 individual release vessels.The individual vessels contained 900 ml of a 0.08 molar HCl solution.The stirring speed was 50 rpm. The temperature was 37° C. The number oftablets tested was 6 tablets per dose. After 20 min, 100 ml of solutionwere removed and filtered through a filter (0.5 μm). This solution wasused without further dilution for direct determination of the amount ofdoxazosin mesylate dissolved out of the tablets. The active ingredientwas determined using a UV spectrophotometer at a wavelength of 245 nm.

The extinctions when the active ingredient has dissolved quantitativelyshould be: 1 mg dose: E 0.116, 2 mg dose: E 0.231 and 4 mg dose: E0.462.

We claim:
 1. A solid pharmaceutical form comprising modification D ofdoxazosin mesylate, wherein the modification D of doxazosin mesylate ischaracterized by lines in an X-ray diffractogram at the following valuesof 2 theta: 5.72±0.2°; 11.10±0.2°; 11.46±0.2°; 14.14±0.2°; 17.01±0.2°;17.78±0.2°; 18.33±0.2°; 20.73±0.2°; 21.70±0.2°; 23.12±0.2°; 24.28±0.2°;26.58±0.2°.
 2. A method of producing solid pharmaceutical forms fortreatment of high blood pressure comprising admixing modification D ofdoxazosin mesylate as claimed in claim 1 with excipients and compressingthe mixture into tablets.